Catalytic Asymmetric Ring-Opening Reactions of Unstrained Heterocycles Using Cobalt Vinylidenes

Abstract

Cobalt catalysts promote highly enantioselective ring-opening reactions of 2,5-dihydrofurans using vinylidenes. The products are acyclic organozinc compounds that can be functionalized with an electrophile. The proposed mechanism involves the generation of a cobalt vinylidene species that adds to the alkene by a [2 + 2]-cycloaddition pathway. Ring-opening then occurs via outer-sphere β-O elimination assisted by coordination of a ZnX₂ Lewis acid to the alkoxide leaving group. DFT models reveal that competing inner-sphere syn β-H and β-O elimination pathways are suppressed by the geometric constraints of the metallacycle intermediate. These models rationalize the observed stereochemical outcome of the reaction.

Graphical Abstract:

Cobalt catalysts promote enantioselective ring-opening reactions of unstrained heterocycles by the reductive addition of 1,1-dichloroalkenes. The products are acyclic homoallylic alcohols containing a vinylzinc motif, which can be further functionalized with an electrophile. Mechanistic studies suggest that ring-opening occurs by an outer-sphere β-O elimination assisted by a Zn(II) Lewis acid.

Strained three-membered heterocycles, such as epoxides^[1] and aziridines,^[2] are common synthetic intermediates that participate in a broad range of ring-opening reactions (Figure 1A).^[3] Extending such processes to larger unstrained rings would provide access to useful alternative bond constructions. However, few examples^[4] are known due to the comparative lack of thermodynamic driving force.^[5] Additionally, three-membered rings feature bent σ-bonding orbitals^[6] that allow them to engage more readily with transition metal catalysts.^[7] In the absence of these distorted bonds, C–X activation becomes more challenging. There are isolated cases where substrates such as 2,5-dihydrofuran can undergo catalytic ring-opening. However, most of these reactions rely on oxophilic Zr species^[8] to induce β-O elimination,^[9] with the one notable exception of a Rh-catalyzed addition of aryl boronic acids.^[10] For other catalytic additions to 2,5-dihydrofuran, competing β-H elimination^[11] is the favored pathway (Figure 1B).^[12]

Figure 1.

A) Catalytic ring-opening reactions of strained vs. unstrained heterocycles. B) Potential competing β-H and β-O elimination pathways. C) Catalytic asymmetric ring-opening reactions of unstrained heterocycles via addition of vinylidenes.

Here, we present an asymmetric addition of vinylidenes to 2,5-dihydrofurans, forming acyclic homoallylic alcohols containing a skipped diene motif (Figure 1C).^[13],[14] A proposed catalytic cycle is illustrated in Figure 2. Reductive activation of the 1,1-dichloroalkene by a (Pybox)Co catalyst (Pybox = pyridine–bis(oxazoline)) generates a cobalt vinylidene species. Previously, we showed that such intermediates can be captured by alkenes to form methylenecyclopropanes by a stepwise [2 + 2]-cycloaddition/C–C reductive elimination pathway.^[15],[16] When the substrate is 2,5-dihydrofuran, C–C reductive elimination does not occur. Instead, β-O elimination induces ring-opening, and the resulting vinylcobalt species undergoes transmetallation to form a vinylzinc product. Key to this process is the formation of a geometrically constrained metallabicyclic intermediate,^[17] which disfavors inner-sphere β-elimination pathways and allows for a cooperative bimetallic outer-sphere β-O elimination.

Figure 2.

Proposed catalytic cycle and competing β-elimination pathways.

Our initial optimization studies focused on identifying a suitable ligand for Co that would provide ring-opened product 3 with high enantioselectivity and control over the E/Z geometry of the alkene. Quinox ligands (5), which were previously used in the vinylidene [2 + 1]- and [5 + 1]-cycloaddition reactions,^[15] provided low yields of 3 and low levels of enantioselectivity (Table 1, entry 2). Significant improvements were observed using tridentate nitrogen-donor ligands (entries 3–6). The Pybox, Bipyox (6), and OIP (7) ligand classes were viable candidates for further investigation, and ^i-PrPybox (4) proved to be optimal, providing product 3 in 80% yield, 96% ee, and a >20:1 E/Z ratio (entry 1).

Table 1.

Effect of reaction parameters.^[a]

entry	changes from Standard Conditions[b]	yield (%)	E:Z	ee (%)
1	none	80	20:1	96
2	ligand 5 instead of 4	11	20:1	25
3	ligand 6 instead of 4	78	20:1	30
4	ligand 7 instead of 4	61	11:1	94
5	ligand 8 instead of 4	70	20:1	82
6	ligand 9 instead of 4	37	20:1	81
7	no Co(dme)Br2	0	–	–
8	no ligand 4	0	–	–
9	2.0 equiv of 2	62	20:1	94
10	without ZnI2	41	20:1	92
11	ZnCl2 instead of ZnI2	60	20:1	94
12	Cp2Co instead of Zn, without ZnI2	0	–	–
13	Cp2Co instead of Zn, with ZnI2	50	20:1	91

^[a]Yields and E:Z ratios of 3 were determined by ¹H NMR analysis of crude reaction mixtures containing 1,3,5-trimethoxybenzene as an internal standard.

^[b]Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 2 (3.0 equiv), Zn (3.0 equiv), ZnI₂ (3.0 equiv), Co(dme)Br₂ (0.15 equiv), 4 (0.18 equiv), DMA (0.75 mL), 40 °C, 24 h.

Control experiments reveal that no product is formed in the absence of Co or the ligand (entries 7–8). Excess 2,5-dihydrofuran (2) is beneficial for yield, and reducing the equivalency decreases the reaction efficiency (entry 9). The excess 2,5-dihydrofuan (2) remains intact at the end of the reaction. Thus, recovery of the excess reaction partner is possible in cases where it is precious. Despite the fact that ZnCl₂ is generated as a reaction byproduct, adding additional Zn(II) salts improves the yield, presumably by aiding in the transmetallation step (entries 10 and 11). Finally, Cp₂Co, which has a similar reduction potential to that of Zn, is ineffective as a reductant when used on its own (entry 12). However, when used in combination with ZnI₂, the yield and ee of 3 is restored (entry 13).

The scope of the asymmetric ring-opening reaction is summarized in Figure 3A. 1,1-Dichloroalkenes substituted with electron-rich or electron-poor aryl groups are effective and consistently provide ee values near 95% and E/Z ratios >20:1. Several functional groups that are potentially reactive toward transition metals, such as boronate esters (product 12), chlorides (product 16), and bromides (product 17),^[18] are well-tolerated in the reaction. Quinoline (product 20), indole (product 21), and benzofuran (product 22) heterocycles can be present in the substrate without deleterious effect. 1,1-Dichloroalkenes containing alkyl substituents provide similarly high levels of enantioselectivity to those containing aryl substituents but display lower yields due to competing cyclopropanation (products 23–24).

Figure 3.

Substrate scope studies. A) Standard reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (3.0 equiv), Zn (3.0 equiv), ZnI₂ (3.0 equiv), Co(dme)Br₂ (0.15 equiv), ligand 4 (0.18 equiv), DMA (1.5 mL), 40 °C, 24 h. Enantiomeric excess values determined by chiral HPLC. Absolute stereochemistry assigned by XRD analysis and then relayed to other compounds by analogy. [a] 10 (0.08 mmol, 1.0 equiv), 4-Nitrobenzoyl chloride (1.1 equiv), NEt₃ (3.0 equiv).^[19] [b] Modified reaction conditions: Co(dme)Br₂ (0.20 equiv), ligand 4 (0.24 equiv). [c] Modified reaction conditions: ZnCl₂ (5.0 equiv) instead of ZnI₂ B) Isotopic labelling and vinylzinc functionalization experiments. C) Regiodivergent ring-opening and parallel kinetic resolution studies using 2-substituted 2,5-dihydrofurans. See supporting information for additional experimental details.

The reaction can be extended to 3-pyrroline 25 to form the corresponding homoallylic amine product 26. Interestingly, 3,6-dihydro-2H-pyran (27) also provides the ring-opened product (28) in high ee. Because alkene 27 is unsymmetrical, the relatively low yield of 28 may be due to low regioselectivity in the alkene addition step. Based on the proposed mechanism, only one regioisomer is capable of undergoing β-O elimination. Finally, vinylidene addition to dioxepine 29 is also viable and provides, after the loss of acetone, the same product (3) as addition to 2,5-dihydrofuran (2), albeit in diminished yield due to greater steric hindrance.

The products of the ring-opening reactions are vinylzinc species that are quenched during aqueous workup (Figure 3B).^[20],[21] When the reaction is instead quenched with CD₃OD in the glovebox, 82% deuteration at C2 is observed (product 3-d₁). Accordingly, the vinylzinc product can be further functionalized with heteroatom or carbon electrophiles. For example, treating the crude product mixture with NIS yields the C2 iodinated product 30. The ee of iodoalkene 30 is identical to that of the proton-quenched product 3. Negishi cross-coupled products can also be generated using MeI (product 31) or 2-bromopyridine (product 32) under standard Pd-catalyzed conditions.

Enantioenriched (S)-33 was prepared to examine the impact of 2-substitution on the course of the ring-opening process (Figure 3C). Using the (S,S)-enantiomer of Pybox ligand 4, primary alcohol 34 is generated in 51% yield, 96% ee, and >20:1 E/Z selectivity. This product corresponds to selective activation of the C2–O bond of (S)-33. Alternatively, the (R,R)-enantiomer of Pybox ligand 4 provides secondary alcohol (R,S)-35 with comparable yields and similarly high levels of enantioselectivity and E/Z selectivity. This result represents a complete turnover in regioselectivity toward activation of the C5–O bond. Finally, the same process can be carried out as a parallel kinetic resolution.^[22] The use of racemic 33 and (S,S)-Pybox 4 yields a mixture of 34 and 35. The Bn-substituted 2,5-dihydrofuran provides similar levels of regio-, enantio-, and E/Z-selectivity (products 36 and 37).

DFT calculations were performed to further probe the mechanism of the catalytic ring-opening (Figure 4A). We hypothesize that the reaction is initiated by the generation of a cobalt vinylidene species (38) from the reductive activation of the 1,1-dichloroalkene. The addition of 2,5-dihydrofuran by a [2 + 2]-cycloaddition mechanism has a barrier of only 7.3 kcal/mol. From the resulting metallacycle 39, we initially considered an inner-sphere β-O elimination pathway. However, the calculated barrier of +31.5 kcal/mol (transition state 40) was prohibitively high and inconsistent with a catalytic process that proceeds at only 40 °C. To avoid the geometric distortions needed to access an inner-sphere syn β-O elimination transition state, we next considered open transition states. The outer-sphere β-O elimination assisted by ZnCl₂ has a barrier of only 15.5 kcal/mol (transition state 41), making it more consistent with experimentally observed rates.

Figure 4.

Mechanistic studies. A) DFT models examining the different β-elimination pathways (M06-L-D3(SMD)/6–311g(d,p). B) A steric model for the origin of asymmetric induction. C) A rationale for the regiodivergent ring-opening reactions of 2-substituted 2,5-dihydrofurans. D) Assessing the facial selectivity of vinylidene additions to alkenes in the context of a reductive conjugate addition reaction.

Notably, the potential competing inner-sphere β-H elimination also has a high barrier of 26.1 kcal/mol (transition state 42) but is favored over inner-sphere β-O elimination. Thus, the high selectivity for ring-opening is not due to an inherent preference for C–O over C–H bond activation. Rather, the constrained geometry of the metallabicyclic intermediate suppresses all inner-sphere pathways, allowing outer-sphere β-elimination pathways to predominate.

To examine the origin of asymmetric induction, four diastereomeric transition states were calculated leading to the four possible stereoisomers of the product (S,E; S,Z; R,E; and R,Z) (Figure 4B). The lowest energy transition state (44) corresponds to the experimentally observed S,E product, and the selectivity can be rationalized by a simple steric model. The 2,5-dihydrofuran approaches the Co=C=CHR fragment on the opposite face as the vinylidene R group and in an open quadrant not occupied by an i-Pr substituent of the Pybox ligand. The approach from the same side as the vinylidene substituent would produce the Z-alkene and is disfavored by 6.6 kcal/mol (transition state 45). Approach from a quadrant occupied by an i-Pr group is disfavored by 15.5 kcal/mol (transition state 46). Finally, the doubly disfavored pathway has the highest barrier with a roughly additive effect of the two steric factors (transition state 47).

Results from the regiodivergent ring-opening reaction of 2-substituted 2,5-dihydrofurans can also be rationalized by the DFT model (Figure 4C). The preference for approach of the substrate away from both the vinylidene R group and the i-Pr group of the ligand also holds for this substrate class. The additional selectivity-determining factor is the orientation of the Bn substituent away from the catalyst. The calculated lowest energy pathways correspond to the experimentally observed regioselectivity of ring-opening as well as the sense of asymmetric induction and the preference for an E-alkene geometry.

A key factor in our DFT model is that the [2 + 2]-cycloaddition step is exothermic and irreversible, indicating that it should be selectivity-determining. To experimentally examine the facial selectivity of the [2 + 2]-cycloaddition step in isolation, we identified an alkene substrate that is reactive toward vinylidenes but is incapable of ring-opening. α,β-Unsaturated lactone 49 reacts under standard catalytic conditions to form the product of a net reductive conjugate addition (Figure 4D). Due to the electronic bias of the alkene, C–C bond formation occurs with high regioselectivity at the β-position, and the resulting Co enolate is not positioned to undergo ring-opening. Upon transmetallation to Zn and quenching with a proton source, the net conjugate addition product 50 is formed in 93% ee.^[23] The absolute stereochemistry was determined by X-ray crystallography and corresponds to the same facial selectivity observed in the ring-opening reaction.

In summary, β-X elimination processes provide a viable mechanism to carry out ring-opening reactions of unstrained five-membered heterocycles. However, β-H elimination is a competing pathway that must be avoided. Here, we show that this selectivity challenge can be addressed using reaction pathways available to cobalt vinylidene species. Addition of a cobalt vinylidene to 2,5-dihydrofuran generates a metallacyclobutane. The structural rigidity of this intermediate suppresses inner-sphere syn β-elimination mechanisms. Instead, a cooperative bimetallic outer-sphere β-O elimination takes place in which a zinc Lewis acid assists in ionization of the leaving group. Ongoing efforts are directed at exploiting the unique properties of metal vinylidene [2 + 2]-cycloadducts in other coupling reactions.